1H-indole-1-functional sPLA2 inhibitors

ABSTRACT

A class of novel 1H-indole-1-functional compounds is disclosed together with the use of such indole compounds for inhibiting sPLA 2  mediated release of fatty acids for treatment of conditions such as septic shock. The compounds are 1H-indole-1-acetamides, 1H-indole-1-acetic acid hydrazides, and 1H-indole-1-glyoxylamides.

This application is a division of application Ser. No. 08/278,353, filedJul. 21, 1994 abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel 1H-indole-1-glyoxylamides,1H-indole-1-acetamides, and 1H-indole-1-hydrazides useful for inhibitingsPLA₂ mediated release of fatty acids for conditions such as septicshock.

2. Background Information

The structure and physical properties of human non-pancreatic secretoryphospholipase A₂ (hereinafter called, "sPLA₂ ") has been thoroughlydescribed in two articles, namely, "Cloning and Recombinant Expressionof Phospholipase A₂ Present in Rheumatoid Arthritic Synovial Fluid" bySeilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley;Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal ofBiological Chemistry, Vol. 264, No. 10, issue of Apr. 5, pp. 5335-5338,1989; and "Structure and Properties of a Human Non-pancreaticPhospholipase A₂ " by Kramer, Ruth M.; Hession, Catherine; Johansen,Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard,Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry,Vol. 264, No. 10, Issue of Apr. 5, pp. 5768-5775, 1989; the disclosuresof which are incorporated herein by reference.

It is believed that sPLA₂ is a rate limiting enzyme in the arachidonicacid cascade which hydrolyzes membrane phospholipids. Thus, it isimportant to develop compounds which inhibit sPLA₂ mediated release offatty acids (e.g., arachidonic acid). Such compounds would be of valuein general treatment of conditions induced and/or maintained byoverproduction of sPLA₂ ; such as septic shock, adult respiratorydistress syndrome, pancreatitis, trauma, bronchial asthma, allergicrhinitis, rheumatoid arthritis, and etc.

The article, "No. 565. -Inhibiteurs d'enzymes. XII. Preparation de(propargyamino-2 ethyl)-3 indoles" by A. Alemanhy, E. Fernandez Alvarez,O. Nieto Lopey and M. E. Rubio Herraez; Bulletin DO La Societe ChimiqqueDe France, 1974, No. 12, pgs. 2883-2888 describes various indolyl-3glyoxamides which are hydrogen substituted on the 6 membered ring of theindole nucleus.

The article "Indol-Umlagerung von1-Diphenylamino-2,3-dihydro-2,3-pyrroldionen" by Gert Kollenz andChrista Labes; Liebigs Ann. Chem., 1975, pgs. 1979-1983 describes phenylsubstituted 3-glyoxylamides.

The abstract, "Nonnarcotic analgesic and antiinflammatory agents.1-Carboxyalkyl-3-acylindoles" by Allais, Andre., et. al., ChemicalAbstracts No. 131402u, Vol. 83, 1975 depicts indole formula with a --CH₂CO₂ H group on the indole nitrogen.

The article, "Structure-activity relationships leading to WAY-121, 520,a tris aryl-type, indomethacin-based, phospholipase A₂(PLA₂)/leukotriene biosynthesis inhibitor", by A Kreft, et. al., Agentsand Actions, Social Conference Issue Vol. 39 (1993),pp. C33-C35, ISSN0065-4299, published by Birkhauser Verlag, Basel Switzerland;(Proceedings of the Sixth International Conference of the InflammationResearch Association, Sep. 20-24, 1992, at White Haven, PA/USA, GuestEditors, D. W. Morgan and A. K. Welton) describes the inhibition ofphospholipase A2 by indomethacin analogs. Indole compounds having benzyland acidic substituents are described.

The article, "Some Analogs of 1-p-chlorobenzyl-5-methylindole-3-aceticacid" by E. Walton, et. al., J. Med. Chem., Vol. 11, 1968, pp.1252-1255, describes the preparation of isomeric methyl3-1-(1-p-chlorobenzyl-5-methoxy-3-methyl indole-2) propionate.

European Patent 490263 discloses oxoacetamide derivatives of indoleshaving serotonin receptor activity.

U.S. Pat. No. 1,825,734 describes the preparation of3-(2-amino-1-hydroxyethyl) indoles using 3-indole glyoxylamideintermediates such as1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see,Example 30).

U.S. Pat. No. 2,890,233 describes several amide derivatives of3-indoleacetic acids.

U.S. Pat. No. 3,271,416 describes indolyl aliphatic acids as sunscreening agents and intermediates. These acids may be --NH₂substituted.

U.S. Pat. No. 3,351,630 describes alpha-substituted 3-indolyl aceticacid compounds and their preparation inclusive of glyoxylamideintermediates.

U.S. Pat. No. 3,449,363 describes trifluoromethylindoles havingglyoxylamide groups at the 3 position of the indole nucleus. Thesecompounds are stated to be analgesics in antagonizing phenyl-p-quinone"writhing syndrome."

World Patent application WO 9206088 describes indole compounds usefulfor treatment of circulatory diseases, chromosis and renal diseases.

Chemical Abstracts Vol. 83, 1975 131402u, "Nonarcotic analgetic andantiinflammatory agents. 1-Carboxyalkyl-3-acylindoles", describesvarious analgesic and antiinflammatory indolencetic acids.

U.S. Pat. No. 4,397,850 prepares isoxazolyl indolamines usingglyoxylamide indoles as intermediates.

U.S. Pat. No. 5,132,319 describes certain 1-(hydroxylaminoalkyl) indolesderivatives as inhibitors of leukotriene biosynthesis.

It is desirable to develop new compounds and treatments for sPLA₂induced diseases.

SUMMARY OF THE INVENTION

This invention is a novel use of compounds known as1H-indole-1-functional compounds wherein the functionality at the1-position (viz., the indole nitrogen) is selected from the groupconsisting of acetamide, acetic acid hydrazide and glyoxylamide asdepicted in the general formula (G) below: ##STR1## These1H-indole-1-functional compounds are effective in inhibiting human sPLA₂mediated release of fatty acids.

This invention is also a novel class of 1H-indole-1-acetamides havingpotent and selective effectiveness as inhibitors of human sPLA₂.

This invention is also a novel class of 1H-indole-1-acetic acidhydrazides (hereinafter called, "hydrazides") having potent andselective effectiveness as inhibitors of human sPLA₂.

This invention is also a novel class of 1H-indole-1-glyoxylamides havingpotent and selective effectiveness as inhibitors of human sPLA₂.

This invention is also a pharmaceutical composition containing a1H-indole-1-functional compound selected from the group consisting ofthe novel 1H-indole-1-acetamides, 1H-indole-1-hydrazides, and1H-indole-1-glyoxylamides of the invention and mixtures thereof.

This invention is also a method of preventing and treating septic shock,adult respiratory distress syndrome, pancreatitis, trauma, bronchialasthma, allergic rhinitis, rheumatoid arthritis, and related diseases bycontact with a therapeutically effective amount of the1H-indole-1-functional aceramides, hydrazides and glyoxylamides of theinvention, or mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

The 1H-indole-1-acetamides, hydrazides, and glyoxylamides of theinvention employ certain defining terms as follows:

The term, "alkyl" by itself or as part of another substituent means,unless otherwise defined, a straight or branched chain monovalenthydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl,tertiary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.

The term, "alkenyl" employed alone or in combination with other termsmeans a straight chain or branched monovalent hydrocarbon group havingthe stated number range of carbon atoms, and typified by groups such asvinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.

The term, "hydrocarbyl" means an organic group containing only carbonand hydrogen.

The term, "halo" means fluoro, chloro, bromo, or iodo.

The term, "heterocyclic radical", refers to radicals derived frommonocyclic or polycyclic, saturated or unsaturated, substituted orunsubstituted heterocyclic nuclei having 5 to 14 ring atoms andcontaining from 1 to 3 hetero atoms selected from the group consistingof nitrogen, oxygen or sulfur. Typical heterocyclic radicals arepyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl,triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl,carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl,thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl,benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl,benzothiazolyl, purinyl, pyridinyl, dipyridinyl, phenylpyridinyl,benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl,1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, andquinoxalinyl.

The term, "carbocyclic radical" refers to radicals derived from asaturated or unsaturated, substituted or unsubstituted 5 to 14 memberedorganic nucleus whose ring forming atoms (other than hydrogen) aresolely carbon atoms. Typical carbocyclic radicals are cycloalkyl,cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl,xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl,phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl,bibenzylyl and related bibenzylyl homologues represented by the formula(bb), ##STR2## where n is a number from 1 to 8.

The term, "non-interfering substituent", refers to radicals suitable forsubstitution at positions 4, 5, 6, and/or 7 on the indole nucleus (ashereinafter depicted in Formula I) and radical(s) suitable forsubstitution on the heterocyclic radical and carbocyclic radical asdefined above. Illustrative non-interfering radicals are C₁ -C₆ alkyl,C₁ -C₆ alkenyl, C₁ -C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁-C₆ alkoxy, C₁ -C₆ alkenyloxy, C₁ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl,C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₁ -C₆ haloalkoxy, C₁ -C₆haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆alkyl), --(CH₂)_(n) --O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio,--(CONHSO₂ R), --CHO, amino, amidino, bromo, carbamyl, carboxyl,ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, --SO₃ H, thioacetal, thiocarbonyl,and C₁ -C₆ carbonyl; where n is from 1 to 8.

The term, "acidic group" means an organic group which when attached toan indole nucleus, through suitable linking atoms (hereinafter definedas the "acid linker"), acts as a proton donor capable of hydrogenbonding. Illustrative of an acidic group are the following: ##STR3##where n is 1 to 8, R₈₉ is a metal or C₁ -C₁₀ alkyl, and R₉₉ is hydrogenor C₁ -C₁₀ alkyl.

The words, "acid linker" refer to a divalent linking group symbolizedas, --(L_(a))--, which has the function of joining the 6 or 7 positionof the indole nucleus to an acidic group in the general relationship:##STR4##

The words, "acid linker length", refer to the number of atoms (excludinghydrogen) in the shortest chain of the linking group --(L_(a))-- thatconnects the 6 or 7 position of the indole nucleus with the acidicgroup. The presence of a carbocyclic ring in --(L_(a))-- counts as thenumber of atoms approximately equivalent to the calculated diameter ofthe carbocyclic ring. Thus, a benzene or cyclohexane ring in the acidlinker counts as 2 atoms in calculating the length of --(L_(a))--.Illustrative acid linker groups are; ##STR5## wherein, groups (a), (b),and (c) have acid linker lengths of 5, 7, and 2, respectively.

The term, "amine", includes primary, secondary and tertiary amines.

Types of 1H-Indole-1-Functional Compounds of the Invention:

There are three types of 1H-indole-1-functional compounds of theinvention described as types (A), (B), and (C) below:

A) 1H-indole-1-acetamide compounds of the invention having the generalformula (I); ##STR6## where each R₁ is independently hydrogen, or C₁ -C₃alkyl; X is selected from oxygen or sulfur; and all other groups are ashereinafter defined.

B) 1H-indole-1-hydrazide compounds of the invention having the generalformula (II); ##STR7## where each R₁ is independently, hydrogen, or C₁-C₃ alkyl; X is selected from oxygen or sulfur; and all other groups areas hereinafter defined.

C) 1H-indole-1-glyoxylamide compounds of the invention having thegeneral formula (III); ##STR8## where each X is independently selectedfrom oxygen and sulfur.

For formulae (I), (II), and (III) above the remaining groups are definedas follows:

R₃ is selected from groups (a), (b) and (c) where;

(a) is C₇ -C₂₀ alkyl, C₇ -C₂₀ alkenyl, C₇ -C₂₀ alkynyl, carbocyclicradicals, or heterocyclic radicals, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group --(L)--R₈₀ ; where, --(L)-- is a divalent linking groupof 1 to 12 atoms and where R₈₀ is a group selected from (a) or (b);

R₂ is hydrogen, halo, C₁ -C₃ alkyl, C₃ -C₄ cycloalkyl, C₃ -C₄cycloalkenyl, --O--(C₁ -C₂ alkyl), --S--(C₁ -C₂ alkyl), or anon-interfering substituent having a total of 1 to 3 atoms other thanhydrogen; (that is, the R₂ radical may contain hydrogen atoms, but theremaining atoms comprising the total of 1 to 3 are non-hydrogen);

R₆ and R₇ are independently selected from hydrogen, a non-interferingsubstituent, or the group, --(L_(a))-(acidic group); wherein--(L_(a))--, is an acid linker having an acid linker length of 1 to 10;provided, that at least one of R₆ and R₇ must be the group,--(L_(a))-(acidic group);

R₄ and R₅ are each independently selected from hydrogen, non-interferingsubstituent, carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents, heterocyclic radical, and heterocyclicradical substituted with non-interfering substituents.

Preferred Subgroups of Compounds of Formulae (I), (II), (III), and (IV):

A preferred subclass of compounds of formulae (I), (II), and (III) arethose wherein all X are oxygen.

Another preferred subclass of compounds of formulae (I), (II), and (III)are those wherein R₂ is selected from the group; halo, cyclopropyl,methyl, ethyl, --O-methyl, and --S-methyl.

Another preferred subclass of compounds of formulae (I), (II) and (III)are those wherein for R₃, --(L)-- is selected from the group consistingof:

    --C.tbd.C--,

    --CH═CH--,

    --CH.sub.2 --,

    --(CH.sub.2).sub.2 --, ##STR9##

    --(CH.sub.2).sub.S --S--,

    --(CH.sub.2).sub.S --O--,

and ##STR10## where s=0 or 1.

Another preferred subclass of compounds of formulae (I), (II), and (III)are those wherein for R₃, group R₈₀ is carbocyclic and is selected fromthe group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl,norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl,terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl,and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologuesrepresented by the formula (bb), ##STR11## where n is a number from 1 to8. Particularly preferred are compounds wherein R₃ is selected from thegroup consisting of ##STR12## where R₁₀ is a radical independentlyselected from halo, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, --S--(C₁ -C₁₀ alkyl),and C₁ -C₁₀ haloalkyl, q is a number from 0 to 4, and t is a number from0 to 5.

Another preferred subclass of compounds of formulae (I), (II), and (III)are those wherein R₇ is a substituent having an acid linker with an acidlinker length of 2 or 3.

Another preferred subclass of compounds of formulae (I), (II), and (III)are those wherein R₇ comprises an acidic group and the acid linker forthe acidic group has an acid linker length of 2 or 3 and the acid linkergroup, --(L_(a))--, for R₇ is selected from the group represented by theformula; ##STR13## where Q is selected from the group --(CH₂)--, --O--,--NH--, and --S--, and R₈₄ and R₈₅ are each independently selected fromhydrogen, C₁ -C₁₀ alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl,carboxy, ethoxycarbonyl, and halo. Most preferred are compounds wherethe acid linker, --(L_(a))--, for R₇ is selected from the specificgroups; ##STR14## where R is H or C₁ -C₄ alkyl.

Another preferred subclass of compounds of formulae (I), (II), and (III)are those wherein R₆ comprises an acidic group and the acid linker ofthe R₆ acidic group has an acid linker with an acid linker length of 3to 10 atoms and the acid linker group, --(L_(a))--, for R₆ is selectedfrom; ##STR15## where r is a number from 1 to 7, s is 0 or 1, and Q isselected from the group --(CH₂)--, --O--, --NH--, and --S--, and R₈₄ andR₈₅ are each independently selected from hydrogen, C₁ -C₁₀ alkyl, aryl,C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl, and halo.Most preferred are compounds where the acid linker, --(L_(a))--, for R₆is selected from the specific groups; ##STR16## wherein; R is hydrogenor C₁ -C₄ alkyl, R₈₄ and R₈₅ are each independently selected fromhydrogen, C₁ -C₁₀ alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl,carboxy, ethoxycarbonyl, and halo.

Another preferred subclass of compounds of formulae (I), (II), (III) arethose wherein the acidic group (or salt, and prodrug derivativesthereof) on R₆ and/or R₇ is selected from the following: ##STR17## wheren is 1 to 8, R₈₉ is a metal or C₁ -C₁₀ alkyl, and R₉₉ is hydrogen or C₁-C₁₀ alkyl. Particularly preferred are compounds wherein the acidicgroup of R₇ or R₈ is selected from;

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O)(OH).sub.2,

or salt, and prodrug (e.g., ester) derivatives thereof. The mostpreferred acidic group is carboxyl. It is highly preferred that only oneof R₆ or R₇ contain an acidic group.

Another preferred subclass of compounds of formula (I) are those whereinR₄ and R₅ are each independently selected from hydrogen andnon-interfering substituents, with the non-interfering substituentsbeing selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆alkenyl, C₁ -C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁-C₆ alkoxy, C₁ -C₆ alkenyloxy, C₁ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl,C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₁ -C₆ haloalkoxy, C₁ -C₆haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆alkyl), --(CH₂)_(n) --O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio,--(CONHSO₂ R), --CHO, amino, amidino, bromo, carbamyl, carboxyl,ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, --SO₃ H, thioacetal, thiocarbonyl,and C₁ -C₆ carbonyl; where n is from 1 to 8.

Preferred compounds of the invention are those having the generalformula (IV), (V), or (VI); ##STR18## wherein for formulae (IV) (V) and(VI); at least one of R₁₆ or R₁₇ must be --(L_(a))-(acidic group); and

R₁₃ is selected from groups (a), (b) and (c) where;

(a) is C₇ -C₂₀ alkyl, C₇ -C₂₀ alkenyl, C₇ -C₂₀ alkynyl; or a carbocyclicradical selected from the group cycloalkyl, cycloalkenyl, phenyl,naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl,stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl,acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and relatedbibenzylyl homologues represented by the formula (bb), ##STR19## where nis a number from 1 to 8; or (b) is a member of (a) substituted with oneor more independently selected non-interfering substituents selectedfrom the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkenyl, C₁ -C₆alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₁ -C₆alkenyloxy, C₁ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂ -C₁₂ alkoxlaminocarbonyl, C₁ -C₁₂ alkylamino, C₁-C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, C₂ -C₆ haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n)--O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio, (--CONHSO₂ R),--CHO, amino, amidino, bromo, carbamyl, carboxyl, ethoxycarbonyl,--(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino,hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro,phosphono, --SO₃ H, thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl; wheren is from 1 to 8; or

(c) is the group --(L₁)--R₈₁ ; where, --(L₁)-- is a divalent linkinggroup having the formula; ##STR20## where, R₈₄ and R₈₅ are eachindependently selected from hydrogen, C₁ -C₁₀ alkyl, aryl, C₁ -C₁₀alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl, and halo;

p is 1 to 5,

Z is a bond, --(CH₂)--, --O--, --N(C₁ -C₁₀ alkyl)--, --NH--, or --S--;and

where R₈₁ is a group selected from (a) or (b);

R₁₂ is hydrogen, halo, C₁ -C₃ alkyl, C₃ -C₄ cycloalkyl, C₃ -C₄cycloalkenyl, --O--(C₁ -C₂ alkyl , or --S--(C₁ -C₂ alkyl;

R₁₇ is selected from hydrogen, a non-interfering substituent, or thegroup, --(L_(a))-(acidic group), wherein the acid linker --(L_(a))-- hasan acid linker length of 2 or 3 atoms and is represented by the formula;##STR21## where Q is selected from the group --(CH₂)--, --O--, --NH--,and --S--; R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, hydroxy, and halo;and the acidic group is selected from

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O)(OH).sub.2,

R₁₆ is selected from hydrogen, a non-interfering substituent, or thegroup, --(L_(a))-(acidic group), wherein the acid linker --(L_(a))-- hasan acid linker length of 3 to 10 atoms and the acid linker group,--(L_(a))-- is; ##STR22## where r is a number from 1 to 7, s is 0 or 1,and Q is selected from the group --(CH₂)--, --O--, --NH--, and --S--;and R₈₄ and R₈₅ are each independently selected from hydrogen, C₁ -C₁₀alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl,and halo; and the acidic group is selected from

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O)(OH).sub.2.

R₁₄ and R₁₅ are each independently selected from hydrogen,non-interfering substituents, selected from the group consisting of C₁-C₆ alkyl, C₁ -C₆ alkenyl, C₁ -C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl, phenyl, toluyl,xylenyl, biphenyl, C₁ -C₆ alkoxy, C₁ -C₆ alkenyloxy, C₁ -C₆ alkynyloxy,C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂alkylthiocarbonyl, C₁ -C₆ aikylsulfinyl, C₁ -C₆ alkylsulfonyl, C₂ -C₆haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n) --O--(C₁ -C₆ alkyl),benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R), --CHO, amino, amidino,bromo, carbamyl, carboxyl, ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro,cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino,hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, --SO₃ H,thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl; where n is from 1 to 8.

Another preferred class of compounds according to this invention are thecompounds represented by formulae (IV), (V) and (VI) where the acidlinker, --(L_(a))--, for R₁₆ is selected from the groups; ##STR23##wherein; R is selected from hydrogen and C₁ -C₄ alkyl; and R₈₄ and R₈₅are each independently selected from hydrogen, C₁ -C₁₀ alkyl, aryl, C₁-C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl, and halo.

Specific preferred compounds and all pharmaceutically acceptable salts,solvates and prodrug derivatives thereof which are illustrative of thecompounds of the invention include the following: ##STR24## and mixturesof the above compounds in any combination.

The salts of the above 1H-indole-1-functional compounds represented byformulae (I), (II), (III), (IV), (V) and (VI) are an additional aspectof the invention. In those instances where the compounds of theinvention possess acidic or basic functional groups various salts may beformed which are more water soluble and physiologically suitable thanthe parent compound. Representative pharmaceutically acceptable salts,include but are not limited to, the alkali and alkaline earth salts suchas lithium, sodium, potassium, calcium, magnesium, aluminum and thelike. Salts are conveniently prepared from the free acid by treating theacid in solution with a base or by exposing the acid to an ion exchangeresin.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Phar.Sci., 66:1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride,clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate,fluoride, fumarate, gluceptate, gluconate, glutamate,glycolylarsanilate, hexylresorcinate, bromide, chloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, malseate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmirate,pantothenate, phosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, tannate, tartrate, rosylate, trifluoroacetate,trifluoromethane sulfonate, and valerate.

Certain compounds of the invention may possess one or more chiralcenters and may thus exist in optically active forms. Likewise, when thecompounds contain an alkenyl or alkenylene group there exists thepossibility of cis- and trans- isomeric forms of the compounds. The R-and S- isomers and mixtures thereof, including racemic mixtures as wellas mixtures of cis- and trans- isomers, are contemplated by thisinvention. Additional asymmetric carbon atoms can be present in asubstituent group such as an alkyl group. All such isomers as well asthe mixtures thereof are intended to be included in the invention. If aparticular stereoisomer is desired, it can be prepared by methods wellknown in the art by using stereospecific reactions with startingmaterials which contain the asymmetric centers and are already resolvedor, alternatively by methods which lead to mixtures of the stereoisomersand subsequent resolution by known methods.

Prodrugs are derivatives of the compounds of the invention which havechemically or metabolically cleavable groups and become by solvolysis orunder physiological conditions the compounds of the invention which arepharmaceutically active in vivo. The prodrug derivative form oftenoffers advantages of solubility, tissue compatibility, or delayedrelease in a mammalian organism (see, Bundgard, H., Design of Prodrugs,pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acidic compound witha suitable alcohol, or amides prepared by reaction of the parent acidcompound with a suitable amine. Simple aliphatic or aromatic estersderived from acidic groups pendent on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy) alkyl esters or((alkoxycarbonyl)oxy)alkyl esters. ##STR25##

Indoles substituted at the 1-position by an alpha substituted acetamideare prepared using the reactions in Scheme 1. The orthonitrotoluene isreduced to the aniline by hydrogen in the presence of Pd/C. The anilineis then converted to 2 by heating with di-tert-butyl dicarbonate intetrahydrofuran (THF). In the case where the R1 group of 2 is hydroxy,the hydroxy group is silylated using t-butyl dimethylsilyl chloride inDMF. The dilithium salt of the dianion of 2 is generated in THF usingsec-butyl lithium and then reacted with an N-methoxy-N-methyl alkanamideto produce 3, which may be converted to 5 using TFA in CH₂ Cl₂.Treatment of 3 with a more dilute solution of TFA in CH₂ Cl₂ gives 4,which can be converted to 5 by warming with base. The conversion of 3 to4 or 5 when R1 is OSiMe₂ t-butyl also results in loss of the silyl groupfrom R1 to give the hydroxy indole, which may be reprotected byalkylation of the sodium salt with benzyl bromide in DMF. Sequentialtreatment of the indoles 5 with n-butyl lithium, zinc chloride, and anaroyl halide affords the 3-acyl indoles 6, which are reduced to 7 by LAHin THF at room temperature. Alkylation of the sodium salt of the indoles7 with an alkyl bromoacetate gives 8. The indoles S are reacted with Me₂AlNH₂ in benzene at 50° C. or are reacted with hydrazine, followed byreduction with Raney nickel to give 10. The R1 group of 10 is reduced toan hydroxy group, either by boron tribromide in CH₂ Cl₂ in the casewhere R1 is methoxy or by hydrogenation in the presence off Pd/C when R1is benzyloxy. The hydroxy 1-H-indole acetamide is then alkylated with anappropriate bromoalkyl ester or phosphonate in the presence of sodiumhydride in DMF, followed by hydrolysis to the acid form such as 11a,11b, and 11c. ##STR26##

Indoles substituted at the 1-position with an alpha. substituted aceticacid hydrazide are prepared as in Scheme 2.

The diester 8, where R1 is OCH₂ CO₂ Et and R is t-butyl is hydrolyzed tothe N-acetic acid compound 9 using trifluoroacetic acid in CH₂ Cl₂.Compound 9 is then reacted with methyl chloroformate and triethyl aminein CH₂ Cl₂, followed by t-butyl carbazate to give the t-butoxycarbonylprotected hydrazide 13. Compound 13 is deesterified at R1 by stirringwith 1N sodium hydroxide in ethanol, then the hydrazide is deprotectedby stirring with trifluoroacetic acid in CH₂ Cl₂ to give the1-H-indole-1-hydrazide 14 as a trifluoroacetic acid salt. ##STR27##

Indoles substituted at the 1-position with a glyoxylamide are preparedas in Scheme 3. The indoles 7 are reduced to the indolines 15 usingNaCNBH₃ in HOAc. Treating 15 with oxalyl chloride followed by ammoniaproduces 16, which is subsequently oxidized by2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dioxane to give the1H-indole-1-glyoxylamides 17.

EXAMPLES

Reference numbers in the following Examples (e.g., "R1", refer tocompounds shown in the preceding Schemes.

Example 1

Preparation of[[1-(2-Amino-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid, a compound represented by the formula: ##STR28## Part APreparation of 2-Hydroxy-6-methyl-N-tert-butoxycarbonylaniline.

A suspension of 20 gm. (0.13 mol) of 2-hydroxy-6-methyl-nitrobenzene and2.5 gm. of 10% Pd/C in 275 ml. of ethanol was shaken under hydrogen at60 psi (414 kPa.) and room temperature for 2 hours. The mixture wasfiltered and evaporated in vacuo. The residue was dissolved in 300 ml.of tetrahydrofuran containing 25 gm. (0.12 mol) of tert-butyldicarbonate, refluxed for 2 hours, cooled, and evaporated in vacuo. Theresidue was chromatographed on silica gel eluting with a gradient20-100% Et2O/hexane to give 2 (R1=7-OH), 19.8 gm., 68% yield.

Analyses for C₁₂ H₁₇ NO₃ : Calculated: C 64.56 H 7.68 N 6.27 Found: C64.29 H 7.47 N 6.26

Part B Preparation of2-tert-butyidimethylsilyloxy-6-methyl-N-tert-butoxycarbonyl aniline.

A solution of 10.4 gm. (47 mmol) of 2 (R1=7-OH), 3.4 gm. (50 mmol) ofimidazole, and 7.6 gm. (50 mmol) of tertbutyldimethylsilyl chloride in150 ml. of dimethylformamide was kept at room temperature for 20 hours,diluted with ethyl acetate, washed with water, washed with brine, driedover sodium sulfate, and evaporated in vacuo. The residue waschromatographed on silica gel eluting with a gradient 5-20% Et₂ O/hexaneto give 2 (R1=7-OSiMe₂ t-butyl), 13.4 gm, 86%,

Analyses for C₁₈ H₃₁ NO₃ Si: Calculated: C 64.05 H 9.26 N 4.15 Found: C64.29 H 9.02 N 4.30

Part C Preparation of1-tert-butoxycarbonyl-2-methyl-7-hydroxy-1H-indole.

A solution of 25 gm. (74 mmol) of 2 (R1=7-OSiMe₂ t-butyl) in 400 ml. oftetrahydrofuran was cooled to -60° C. and treated with 143 ml. of 1.3Msec-butyl lithium in hexane. The mixture was allowed to warm to -20° C.and then recooled to -60° C. A solution of 8.2 gm. (80 mmol) ofN-methyl-N-methoxyacetamide in 50 ml. of tetrahydrofuran was addedslowly, the cooling bath was removed, the mixture stirred for 1.5 hours,diluted with water, and extracted with ethyl acetate. The organic phasewas washed with brine, dried over sodium sulfate, and evaporated invacuo to give 3 (R1=7-OSiMe₂ t-butyl, R2=MeCOCH₂) as a residue which wasdissolved in 125 ml. of dichloromethane and treated with 10 ml. oftrifluoroacetic acid for 45 minutes. The solution was washed withaqueous sodium bicarbonate, washed with brine, dried over sodiumsulfate, and evaporated in vacuo. The residue was chromatographed oversilica gel eluting with a gradient 10-15% Et₂ O/hexane to give 4(R1=7-OH, R2=Me), 10.3 gm., 70% yield.

Analyses for C₁₄ H₁₇ NO₃ : Calculated: C 67.99 H 6.92 N 5.61 Found: C66.31 H 6.83 N 5.87

Part D Preparation of 2-methyl-7-benzyloxy-1H-indole.

A solution of 10.3 gm. (42 mmol) of 4 (R1=7-OH, R2=Me). in 150 ml. ofdimethylformamide and 20 ml. of tetrahydrofuran was treated with 1.8 gm.of sodium hydride (60% in mineral oil; 45 mmol) for 10 minutes and thenwith 5.5 ml. (46 mmol) of benzyl bromide for 3.5 hours, diluted withethyl acetate, washed with water, washed with brine, dried over sodiumsulfate, and evaporated in vacuo to give 4 (R1=7-benzyloxy, R2=Me) as aresidue which was dissolved in 200 ml. of ethanol containing 50 ml of 5Nsodium hydroxide, refluxed for 17 hours, cooled, acidified with 5Nhydrochloric acid, and extracted with ethyl acetate. The organic phasewas washed with brine, dried over sodium sulfate, and evaporated invacuo. The residue was chromatographed on silica gel eluting with agradient 10-20% Et₂ O/hexane to give 5 (R1=7-OCH₂ C₆ H₅, R₂ =Me), 7.7gm., 78% yield.

Analyses for C₁₆ H₁₅ NO: Calculated: C 74.75 H 6.87 N 4.15 Found: C75.03 H 6.66 N 4.24

Part E Preparation of 2-methyl-3-benzoyl-7-benzyloxy-1H-indole.

A solution 7.7 gm. (32 mmol) of 5 (R1=7-OCH₂ C₆ H₅, R2=Me) in 200 ml. oftetrahydrofuran was cooled to -5 C. and treated with 21 ml. of n-butyllithium followed by 35 ml. of 1M zinc chloride in Et₂ O, stirred 2.5hours at room temperature, and evaporated in vacuo. The residue wasdissolved in 200 ml. of toluene and treated with 4 ml. (34 mmol) ofbenzoyl chloride for 21 hours, stirred well with aqueous sodiumbicarbonate and extracted with ethyl acetate. The organic phase waswashed with brine, dried over sodium sulfate, and evaporated in vacuo.The residue was chromatographed on silica gel eluting with a gradient20-50% Et₂ O/hexane to give 6 (R1=7-OCH₂ C₆ H₅, R2=Me, Ar═C₆ H₅), 4.6gm., 43% yield, amorphous solid.

Analyses for C₂₃ H₁₉ NO₂ : Calculated: C 80.92 H 5.61 N 4.10 Found: C80.99 H 5.90 N 3.89

Part F Preparation of 2-methyl-3-phenylmethyl-7-benzyloxy-1H-indole.

A solution of 4.6 gm. (13 mmol) of 6 (R1=7-OCH₂ C₆ H₅, R2=Me, Ar═C₆ H₅)in 200 ml. of tetrahydrofuran containing 2 gm. of lithium aluminumhydride was stirred for 19.5 hours, cooled in ice water, and decomposedby the sequential addition of ethyl acetate and then 5N sodiumhydroxide. The solution was decanted, washed with brine, dried oversodium sulfate, and evaporated in vacuo. The residue was chromatographedon silica gel eluting with a gradient 5-15% Et₂ O/hexane to give 7(R1=7-OCH₂ C₆ H₅, R2=Me, Ar═C₆ H₅), 3.4 gm., 77% yield, mp 124°-125°C./Et₂ O-EtOH.

Analyses for C₂₃ H₂₁ NO: Calculated: C 84.37 H 6.46 N 4.28 Found: C84.15 H 6.69 N 4.26

Part G Preparation of[2-methyl-3-(phenylmethyl)-7-benzyloxy-1H-indol-1-yl]acetic acid ethylester.

A solution of 1.3 gm. (3 mmol) of 7 (R1=7-OCH₂ C₆ H₅, R2=He, Ar═C₆ H₅)in 70 ml. of dimethylformamide and 10 ml. of tetrahydrofuran was treatedwith 130 mg. of sodium hydride 60% in mineral oil; 3.3 mmol) for 15minutes and then with 0.55 ml. (3.4 mmol) of ethyl bromoacetate for 1.25hours, diluted with ethyl acetate, washed with water, washed with brine,dried over sodium sulfate, and evaporated in vacuo. The residue waschromatographed on silica gel eluting with a gradient 5-15% Et2O/hexaneto give 8 (R1=7-OCH₂ C₆ H₅, R=Et, R2=Me, Ar═C₆ H₅, X=OEt), 890 mg., 58%yield, mp 92°-93° C./CH₂ Cl₂ -EtOH.

Analyses for C₂₇ H₂₇ NO₃ : Calculated: C 78.42 H 6.58 N 3.39 Found: C78.63 H 6.55 N 3.36

Part H Preparation of[2-methyl-3-(phenylmethyl)-7-benzyloxy-1H-indol-1-yl]acetamide.

A solution of 880 mg. (2.2 mmol) of 8 (R1=7-OCH₂ C₆ H₅, R=Et, R₂ =Me,Ar═C₆ H₅, X=OEt) in 40 ml. of benzene was treated with 15 ml. of a ca.0.67M solution of Me₂ AlNH₂ in 2:1 benzene:toluene at 50° C. for 21hours, cooled in ice-water, decomposed with ice-1N hydrochloric acid,and extracted with ethyl acetate. The organic phase was washed withbrine, dried over sodium sulfate, and evaporated in vacuo. The residuewas chromatographed on silica gel eluting with Et₂ O and then ethylacetate to give 10 (R1=7-OCH₂ C₆ H₅, R2=Me, Ar═C₆ H₅, X═NH₂), 650 mg.,80% yield, mp 167°-168° C./EtOAc.

Analyses for C₂₅ H₂₄ N₂ O₂ : Calculated: C 78.10 H 6.29 N 7.29 Found: C77.36 H 6.50 N 7.07

Part I Preparation of[2-Methyl-3-(phenylmethyl)-7-hydroxy-1H-indol-1-yl]acetamide:

A mixture of 0.5 gm. of 10% Pd/C and 625 mg. of 10 (R1=7-OCH₂ C₆ H₅,R2=Me, Ar═C₆ H₅, X═NH₂) in 75 ml. of tetrahydrofuran and 75 ml. ofethanol was shaken under 42-47 psi (289-324 KPa.) of hydrogen for 5.5hours, filtered, and evaporated in vacuo. The residue waschromatographed on silica gel eluting with ethyl acetate to give 10(R1=7-OH, R2=Me, Ar═C₆ H₅, X═NH₂), 370 mg., 77% yield, mp 189°-191°C./EtOAc.

Analyses for C₁₈ H₁₈ N₂ O₂ : Calculated: C 73.45 H 6.16 N 9.52 Found: C73.28 H 6.30 N. 9.33

Part J Preparation of[[1-(2-Amino-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid tert-butyl ester, compound represented by the formula: ##STR29##

A solution of 370 mg. (1.3 mmol) of 10 (R1=7-OH, R₂ =Me, Ar═C₆ H₅,X═NH₂) in 70 ml. of dimethylformamide and 10 ml. of tetrahydrofuran wastreated with 60 mg. of sodium hydride (69% in mineral oil; 1.5 mmol) for15 minutes and then with 0.25 ml. of tert-butyl bromoacetate for 2.5hours, diluted with ethyl acetate, washed with water, washed with brine,dried over sodium sulfate, and evaporated in vacuo to give 10 (R1=-OCH₂CO₂ t-butyl, R2-Me, Ar═C₆ H₅, X═NH₂), 340 mg., 66% yield, mp 113°-115°C./Et₂ O-hexane.

Analyses for C₂₄ H₂₈ N₂ O₄ : Calculated: C 70.57 H 6.91 N 6.86 Found: C70.33 H 7.02 N 6.76

Part K Preparation of[[1-(2-amino-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid.

A solution of 340 mg. of 10 (R1=7-OCH₂ CO₂ t-butyl, R2=Me, Ar═C₆ H₅,X═NH₂) in 30 ml. of dichloromethane and 2-3 ml. of trifluoroacetic acidwas stirred 2.5 hours and then evaporated in vacuo to give 11a (R2=Me,Ar═C₆ H₅, X═NH₂), 220 mg., 76% yield, mp 190°-192° C./EtOAc.

Analyses for C₂₀ H₂₀ N₂ O₄ : Calculated: C 68.17 H 5.72 N 7.95 Found: C68.42 H 5.84 N 8.09

Example 2

This Example illustrates the preparation of an acetamide compound withthe acidic group in the 6 position.

Preparation of4-[[1-(2-amino-2-oxoethyl)-2-ethyl-3-(phenylmethyl)-1H-indol-6-yl]oxy]butyricacid, a compound represented by the formula: ##STR30## Part APreparation of N-tert-butoxycarbonyl-2-methyl-5-methoxyaniline.

A mixture of 10 gm. (60 mmol) of 3-nitro-4-methylanisole and 4 gm. of10% Pd/C was stirred under 1 atm. of hydrogen for 30 hours, filtered,and evaporated in vacuo to give 3-amino-4-methylanisole as a residuewhich was dissolved in 250 ml. of tetrahydrofuran containing 13 gm. (60mmol) of tert-butyl dicarbonate, refluxed for 3 hours, cooled, andevaporated in vacuo. The residue was chromatographed on silica geleluting with a gradient 5-10% Et₂ O /hexane to give 2 (R1=5-OMe), 10.3gm., 72% yield, mp 72°-74° C.

Analyses for C₁₃ H₁₉ NO₃ : Calculated: C 65.80 H 8.07 N 5.90 Found: C65.55 H 8.00 N 6.00

Part B Preparation of 2-ethyl-6-methoxy-1H-indole.

A solution of 5.4 gm. (23 mmol) of 2 (R1=5-OMe) in 150 ml. oftetrahydrofuran was cooled to -75° C. and treated slowly with 36 ml. ofsec-butyl lithium (1.3M in hexane; 47 mmol), allowed to warm to -20 C.,recooled to -75° C., and treated slowly with a solution of 2.9 gm. (25mmol) of N-methyl-N-methoxypropranamid in 50 ml. of tetrahydrofuran,stirred without cooling for 25 minutes, diluted with water, andextracted with ethyl acetate. The organic phase was washed with brine,dried over sodium sulfate, and evaporated in vacuo to give 3 (R1=5-OMe,R2=Et), as a residue. The residue was dissolved in 125 ofdichloromethane and 10 ml. of trifluoroacetic acid, stirred 10 minutes,washed with aqueous sodium bicarbonate, washed with brine, dried oversodium sulfate, and evaporated in vacuo to give to give 4 (R1=6-OMe,R2=Et) as a residue which was dissolved in 50 ml. of ethanol containing5 ml. of 5N sodium hydroxide, refluxed 2.5 hours, cooled, acidified with5N hydrochloric acid, and extracted with ethyl acetate. The organicphase was washed with brine, dried over sodium sulfate, and evaporatedin vacuo. The residue was chromatographed on silica gel eluting with agradient 15-20% Et₂ O/hexane to give 5 R1=6-OMe, R2=Et), 840 mg., 21%yield, mp 77°-79° C./Et₂ O-hexane.

Analyses for C₁₁ H₁₃ NO: Calculated: C 75.40 H 7.48 N 7.99 Found: C75.18 H 7.53 N 7.99

Part C Preparation of 2-ethyl-3-benzoyl-6-methoxy-1H-indole.

A solution of 840 mg. (4.8 mmol) of 5 (R1=6-OMe, R2=Et) in 100 ml. oftetrahydrofuran was treated sequentially with 3.0 ml. of 1.6M n-butyllithium/hexane and 5.0 ml. of 1.0M ZnCl₂ /Et₂ O at -5° C., stirred atroom temperature for 2 hours, evaporated in vacuo, dissolved in 100 ml.of toluene, and treated with 0.6 ml. of benzoyl chloride for 17.5 hours.The mixture was stirred well with aqueous sodium bicarbonate andextracted with ethyl acetate. The organic phase was washed with brine,dried over sodium sulfate, and evaporated in vacuo. The residue waschromatographed on silica gel eluting with a gradient 20-60% Et₂O/hexane to give 6 (R1=6-OMe, R2=Et, Ar═C₆ H₅), 435 mg., 33% yield, mp167-169/CH₂ Cl₂ -EtOH.

Analyses for C₁₈ H₁₇ NO₂ : Calculated: C 77.40 H 6.13 N 5.01 Found: C77.70 H 6.27 N 5.28

Part D Preparation of 2-ethyl-3-(phenylmethyl)-6-methoxy-1H-indole.

A solution of 435 mg. of 6 (R1=6-OMe, R2=Et, Ar═C₆ H₅) in 75 ml. oftetrahydrofuran containing 0.4 gm. of lithium aluminum hydride wasstirred for 24 hours, cooled in ice-water, and decomposed by thesequential addition of ethyl acetate and 5N sodium hydroxide. Thesolution was decanted, washed with brine, dried over sodium sulfate, andevaporated in vacuo. The residue was chromatographed on silica geleluting with a gradient 10-25% Et₂ O/hexane to give 7 (R1=6-OMe, R2=Et,Ar═C₆ H₅), 160 mg., 38% yield, mp 101°-103° C./Et₂ O-hexane.

Analyses for C₁₈ H₁₉ NO: Calculated: C 81.48 H 7.22 N 5.28 Found: C81.31 H 7.85 N 5.30

Part E Preparation of[2-ethyl-3-(phenylmethyl)-6-methoxy-1H-indol-1-yl]acetic acid methylester.

To a solution of 1.59 g. (6 mmol) of 7 (R1=6-OMe, R2=Et, Ar═C₆ H₅) in 15ml. of dimethyl formamide was added 240 mg. (6 mmol) of 60% sodiumhydride/mineral oil. Stirred at room temperature for 80 min., then added0.57 ml. (6 mmol) of methyl. bromoacetate and continued to stir for 22hours. Water and ethyl acetate were added. The ethyl acetate layer wasseparated, washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue was chromatographed on silica gel,eluting with 20% EtOAc/hexane to give 8 (R1=6-OMe, R=Me, R2=Et, Ar═C₆H₅), 931 mg., 46% yield, mp 90°-94° C.

Analyses for C₂₁ H₂₃ NO₃ : Calculated: C 74.75 H 6.87 N 4.15 Found: C73.83 H 6.90 N 4.04

Part F Preparation of[2-ethyl-3-(phenylmethyl)-6-methoxy-1H-indol-1-yl]acetic acid hydrazide

A solution of 1.33 g. (3.9 mmol) of 8 (R1=6-OMe, R=Me, R2=Et, Ar═C₆ H₅)in 20 ml. of ethanol containing 4 ml. of hydrazine was heated at refluxfor 4 hours. The solution was evaporated to dryness in vacuo. Theresidue was dissolved in EtOAc/H₂ O. The ethyl acetate layer wasseparated, washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue was crystallized from methanol to give[2-ethyl-3-(phenylmethyl)-6-methoxy-1H-indol-1-yl]acetic acid hydrazide(R1=6-OMe, R2=Et, Ar═C₆ H₅), 1.05 g., 80% yield, mp 164°-166° C.

Analyses for C₂₀ H₂₃ N₃ O₂ : Calculated: C 71.19 H 6.87 N 12.45 Found: C72.15 H 7.06 N 12.92

Part G Preparation of[2-ethyl-3-(phenylmethyl)-6-methoxy-1H-indol-1-yl]acetamide

A suspension of 688 mg. (2 mmol) of[2-ethyl-3-(phenylmethyl)-6-methoxy-1H-indol-1-yl]acetic acid hydrazide(from Part F, R=6-OMe, R2=Et, Ar═C₆ H₅) and approximately 700 mg. ofRaney nickel in 25 ml. of ethanol was heated at reflux for 1.5 hours.The ethanol solution was decanted from the Raney nickel, then the Raneynickel was washed 3 times with methylene chloride, each time decantingthe wash solution into the ethanol solution. The combined organics werefiltered free of residual. Raney nickel,then evaporated in vacuo. Theresidue was dissolved in ethyl acetate containing 10% methanol andwashed with water and brine, then dried over magnesium sulfate andevaporated in vacuo to give 10 (R1=6-OMe, R2=Et, Ar═C₆ H₅), 566 mg., 88%yield, mp 190°-192° C.

Analyses for C₂₀ H₂₂ N₂ O₂ : Calculated: C 74.51 H 6.88 N 8.69 Found: C74.23 H 6.91 N 8.91

Part H Preparation of[2-ethyl-3-(phenylmethyl)-6-hydroxy-1H-indol-1-yl]acetamide

To a solution of 551 mg. (1.7 mmol) of 10 (R1=6-OMe, R2=Et, Ar═C₆ H₅) in30 ml. of methylene chloride was added 6 ml. of a 1M solution of borontribromide in methylene chloride (6 mmol). The solution was stirred for4 hours, then an additional 1.5 ml. of the boron tribromide solution wasadded. After stirring an additional 2.5 hours, the solution wasevaporated to dryness in vacuo. The residue was dissolved in ethylacetate and washed with water and brine, then dried over magnesiumsulfate and evaporated in vacuo. The product, 10 (R1=6-OH, R2=Et, Ar═C₆H₅) was crystallized from methanol, yielding 422 mg., 80% yield , mp215°-217° C.

Analyses for C₁₉ H₂₀ N₂ O₂ : Calculated: C 74.00 H 6.54 N 9.08 Found: C73.79 H 6.80 N 8.92

Part I Preparation of4-[[1-(2-amino-2-oxoethyl)-2-ethyl-3-(phenylmethyl)-1H-indol-6-yl]oxy]butyricacid ethyl ester

To a suspension of 24 mg.(0.6 mmol) of 60% sodium hydride/mineral oil in15 ml. of dimethyl formamide was added 185 mg. (0.6 mmol) of 10(R1=6-OH, R2=Et, Ar═C₆ H₅). The suspension was stirred 2 hours at roomtemperature, then there was added 0.09 ml. (0.6 mmol) ofethyl-4-bromobutyrate, stirred for 3.5 hours, then there was added waterand ethyl acetate. The ethyl acetate layer was separated, washed withbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was chromatographed over silica gel, eluting with 50%EtOAc/hexane followed by EtOAc to give 10 (R1=6-OCH₂ CH₂ CH₂ CO₂ Et,R2=Et, Ar═C₆ H₅), 70 mg., 28% yield, mp 105°-119° C.

Analyses for C₂₅ H₃₀ N₂ O₄ : Calculated: C 71.07 H 7.16 N 6.63 Found: C72.54 H 7.53 N 6.93

Part J Preparation of4-[[1-(2-amino-2-oxoethyl)-2-ethyl-3-(phenylmethyl)-1H-indol-6-yl]oxy]butyricacid

A suspension of 60 mg.(0.14 mmol) of 10 (R1=6-OCH₂ CH₂ CH₂ CO₂ Et,R2=Et, Ar═C₆ H₅) in 3 ml. of methanol and 1 ml. of 1N sodium hydroxidewas heated to give a complete solution, then stirred at room temperaturefor 1 hour. Ethyl acetate and water were added to the reaction mixture.The ethyl acetate layer was removed and the aqueous layer was acidifiedto pH 2.5 with 1N hydrochloric acid and extracted with ethyl acetate.The ethyl acetate extract was washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was stirred with methanoland filtered off to give 11b (R1=6-OCH₂ CH₂ CH₂ CO₂ H, R2=Et, Ar═C₆ H₅),40mg., 73% yield, mp 174°-176° C.

Analyses for C₂₃ H₂₆ N₂ O₄ : Calculated: C 70.03 H 6.64 N 7.10 Found: C70.35 H 6.60 N 7.33

Example 3

Preparation of[3-[[1-(2-amino-2-oxoethyl)-2-ethyl-3-(phenylmethyl)-1H-indol-6-yl]oxy]propyl]phosphonicacid, a compound represented by the formula: ##STR31## Part APreparation of[3-[[1-(2-amino-2-oxoethyl)-2-ethyl-3-(phenylmethyl)-1H-indol-6-yl]oxy]propyl]phosphonicacid dimethyl ester

To a suspension of 29 mg. (0.71 mmol) of 60% sodium hydride/mineral oilin 5 ml of dimethylformamide was added 219 mg. (0.71 mmol) of 10(R1=6-OH, R2=Et, Ar═C₆ H₅) in 5 ml of dimethylformamide. Stirred for 30minutes at room temperature, then added 196 mg. (0.85 mmol) of3-bromopropylphosphonic acid dimethyl ester. Stirred for 2 hours, thenadded water and ethyl acetate. The ethyl acetate layer was separated,washed with brine, dried over magnesium sulfate, and evaporated invacuo. The residue was chromatographed on silica gel, eluting with EtOAcfollowed by 5% MeOH/EtOAc to give 10 (R1=6-OCH₂ CH₂ CH₂ PO₃ Me₂, R2=Et,Ar═C₆ H₅), 248 mg., 76%, mp 118°-119° C.

Analyses for C₂₄ H₃₁ N₂ O₅ P: Calculated: C 62.87 H 6.32 N 6.11 Found: C63.12 H 6.74 N 6.10

Part B Preparation of[3-[[1-(2-amino-2-oxoethyl)-2-ethyl-3-(phenylmethyl)-1H-indol-6-yl]oxy]propyl]phosphonicacid

A solution of 240 mg.(0.52 mmol) of 10 (R1=6-OCH₂ CH₂ CH₂ PO₃ Me2,R2=Et, Ar═C₆ H₅) and 0.55 ml (4.19 mmol) of bromotrimethylsilane in 5 mlof methylene chloride was stirred for 16 hours. The reaction mixture wasconcentrated at reduced pressure, 5 ml methanol added, stirred 1 hour,and concentrated. The residue was crystallized from EtOAc/MeCN/HOAc/H2Oto give 167 mg, 75% yield of 11c, mp 183°-186° C.

Analyses for C₂₂ H₂₇ N₂ O₅ P: Calculated: C 61.39 H 6.32 N 6.51 Found: C61.61 H 6.06 N 6.27

Example 4

Preparation of[[1-(2-hydrazino-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid, a compound represented by the formula: ##STR32## Part APreparation of[[1-(2-hydroxy-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid ethyl ester.

A solution of 460 mg. (1.05 mmol of[[1-(2-tertbutyloxy-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid ethyl ester 8 in 10 ml of methylene chloride and 2 ml oftrifluoroacetic acid was stirred at room temperature for 2.5 hours. Thesolvent and excess trifluoroacetic acid were evaporated in vacuo. Theresidue was dissolved in ethyl acetate and washed with water and brine,then dried over MgSO₄ and evaporated to give 396 mg. (99% yield) of 9(R1=7-OCH₂ CO₂ Et, R2=Me, Ar═C₆ H₅) as an oil.

Analyses for C₂₂ H₂₃ NO₅ : Calculated: C 69.28 H 6.08 N 3.67 Found: C69.03 H 6.27 N 3.71

Part B Preparation of[[1-[2-(2-tert-butoxycarbonylhydrazino)-2-oxoethyl]-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid ethyl ester.

To a solution of 381 mg. (1 mmol) of 9 (R1=7-OCH₂ CO₂ Et, R2=Me, Ar═C₆H₅) in 50 ml. of methylene chloride was added 0.16 ml. (1.2 mmol) oftriethylamine. The solution was cooled to -5° C. and 0.1 ml. (1.3 mmol)of methyl chloroformate was added. The solution was stirred for 5 min.,then 132 mg. (1 mmol) of tertbutyl carbazate was added and the mixturestirred at room temperature for 30 min. The solution was washed withwater and brine, then dried over MgSO₄ and evaporated. The residue waschromatographed on silica gel, eluted with 50% EtOAc/hexane to give 428mg. (86% yield) of[[1-(2-N-tertbutyloxycarbonylhydrazino-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid ethyl ester 13 as an oil.

Analyses for C₂₇ H₃₃ N₃₃ O₆ : Calculated: C 65.44 H 6.71 N 8.48 Found: C65.58 H 6.87 N 8.30

Part C Preparation of[[1-(2-hydrazino-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid.

A solution of 380 mg. of1-(2-tertbutyloxycarbonylhydrazino-2-oxoethyl)-2-methyl-3-(phenylmethyl)-1H-indol-7-yl]oxy]aceticacid ethyl ester 13 in 15 ml of ethanol and 4 ml of 1N NaOH was stirredat room temperature for 1 hour. The solution was diluted with water andextracted with ethyl acetate, washed with brine, dried (HgSO₄) andevaporated. The residue was stirred with 5 ml of trifluoroacetic acidfor 1 hour. The solution was evaporated in vacuo and the residue wasdissolved in EtOAc/H₂ O. The EtOAc extract was separated, washed withbrine, dried over MgSO₄ and evaporated to give a solid. The solid wasstirred with ether and filtered off to give 143 mg. (51% yield) of 14(R1=7-OCH₂ CO₂ H, R2=Me, Ar═C₆ H₅) as a trifluoroacetic acid salt.

Analyses for C₂₂ N₂₂ F₃ N₃ O₆ : Calculated: C 54.89 H 4.60 N 8.73 Found:C 56.03 H 5.04 N 8.89

Therapeutic Use of 1H-indole-1-functional compounds

1H-indole-1-functional compounds described herein are believed toachieve their beneficial therapeutic action principally by directinhibition of human sPLA₂, and not by acting as antagonists forarachidonic acid, nor other active agents below arachidonic acid in thearachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, andetc.

The method of the invention for inhibiting sPLA₂ mediated release offatty acids comprises contacting sPLA₂ with an therapeutically effectiveamount cf 1H-indole-1-functional compound corresponding to Formulae (I),(II), (III), (IV), (IV), or (VI) substituted am the 6 or 7 positionswith an acidic derivative, its salt or a prodrug derivative thereof.

The compounds of the invention may be used in a method of treating amammal (e.g., a human) to alleviate the pathological effects of septicshock, adult respiratory distress syndrome, pancreatitus, trauma,bronchial asthma, allergic rhinitis, and rheumatoid arthritis; whereinthe method comprises administrating to the mammal at least one1H-indole-1-functional compound represented by formulae (II), (II),(III), (IV), (V) or (VI) or any combination thereof in a therapeuticallyeffective amount. A therapeutically effective amount is an amountsufficient to inhibit sPLA₂ mediated release of fatty acid and tothereby inhibit or prevent the arachidonic acid cascade and itsdeleterious products. The therapeutic amount of compound of theinvention needed to inhibit sPLA₂ may be readily determined by taking asample of body fluid and assaying it for sPLA₂ content by conventionalmethods.

Pharmaceutical Formulations of the Invention

As previously noted the compounds of this invention are useful forinhibiting sPLA₂ mediated release of fatty acids such as arachidonicacid. By the term, "inhibiting" is meant the prevention ortherapeutically significant reduction in release of sPLA₂ initiatedfatty acids by the compounds of the invention. By "pharmaceuticallyacceptable" it is meant the carrier, diluent or excipient must becompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The specific dose of a compound administered according to this inventionto obtain therapeutic or prophylactic effects will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the route ofadministration and the condition being treated. Typical daily doses willcontain a non-toxic dosage level of from about 0.01 mg/kg to about 50mg/kg of body weight of an active compound of this invention.

Preferably the pharmaceutical formulation is in unit dosage form. Theunit dosage form can be a capsule or tablet itself, or the appropriatenumber of any of these. The quantity of active ingredient in a unit doseof composition may be varied or adjusted from about 0.1 to about 1000milligrams or more according to the particular treatment involved. Itmay be appreciated that it may be necessary to make routine variationsto the dosage depending on the age and condition of the patient. Thedosage will also depend on the route of administration.

The compound can be administered by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,and intranasal.

Pharmaceutical formulations of the invention are prepared by combining(e.g., mixing) a therapeutically effective amount of the1H-indole-1-functional compounds of the invention together with apharmaceutically acceptable carrier or diluent therefor. The presentpharmaceutical formulations are prepared by known procedures using wellknown and readily available ingredients.

In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, or can be in the form of tablets, pills, powders, lozenges,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), or ointment, containing, for example, up to 10%by weight of the active compound. The compounds of the present inventionare preferably formulated prior to administration.

For the pharmaceutical formulations any suitable Tarrier known in theart can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. Solid form formulationsinclude powders, tablets and capsules. A solid carrier can be one ormore substances which may also act as flavoring agents, lubricants,solubilisers, suspending agents, binders, tablet disintegrating agentsand encapsulating material.

Tablets for oral administration may contain suitable excipients such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or acacia, andlubricating agents such as magnesium stearate, stearic acid, or talc.

In powders the carrier is a finely divided solid which is in admixturewith the finely divided active ingredient. In tablets the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from about 1 toabout 99 weight percent of the active ingredient which is the novelcompound of this invention. Suitable solid carriers are magnesiumcarbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin,starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, low melting waxes, and cocoa butter.

Sterile liquid form formulations include suspensions, emulsions, syrupsand elixirs.

The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent or a mixture of both. The active ingredient can often bedissolved in a suitable organic solvent, for instance aqueous propyleneglycol. Other compositions can be made by dispersing the finely dividedactive ingredient in aqueous starch or sodium carboxymethyl cellulosesolution or in a suitable oil.

The following pharmaceutical formulations 1 thru 8 are illustrative onlyand are not intended to limit the scope of the invention in any way."Active ingredient", refers to a compound according to Formula (I) or apharmaceutically acceptable salt, solvate, or prodrug thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                           Quantity                                                                      (mg/capsule)                                               ______________________________________                                        Active ingredient    250                                                      Starch, dried        200                                                      Magnesium stearate    10                                                      Total                460     mg                                               ______________________________________                                    

Formulation 2

A tablet is prepared using the ingredients below:

    ______________________________________                                                            Quantity                                                                      (mg/tablet)                                               ______________________________________                                        Active ingredient     250                                                     Cellulose, microcrystalline                                                                         400                                                     Silicon dioxide, fumed                                                                               10                                                     Stearic acid           5                                                      Total                 665     mg                                              ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg

Formulation 3

An aerosol solution is prepared containing the following components:

    ______________________________________                                                              Weight                                                  ______________________________________                                        Active ingredient       0.25                                                  Ethanol                 25.75                                                 Propellant 22 (Chlorodifluoromethane)                                                                 74.00                                                 Total                   100.00                                                ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to -30° C. and transferred no afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient          60     mg                                          Starch                     45     mg                                          Microcrystalline cellulose 35     mg                                          Polyvinylpyrrolidone (as 10% solution in water)                                                          4      mg                                          Sodium carboxymethyl starch                                                                              4.5    mg                                          Magnesium stearate         0.5    mg                                          Talc                       1      mg                                          Total                      150    mg                                          ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient       80     mg                                             Starch                  59     mg                                             Microcrystalline cellulose                                                                            59     mg                                             Magnesium stearate      2      mg                                             Total                   200    mg                                             ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 6

Suppositories, each containing 225 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient       225    mg                                             Saturated fatty acid glycerides                                                                       2,000  mg                                             Total                   2,225  mg                                             ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture: is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of active ingredient per 5 ml dose,are made as follows:

    ______________________________________                                        Active ingredient        50 mg                                                Sodium carboxymethyl cellulose                                                                         50 mg                                                Syrup                    1.25 ml                                              Benzoic acid solution    0.10 ml                                              Flavor                   q.v.                                                 Color                    q.v.                                                 Purified water to total  5 ml                                                 ______________________________________                                    

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 8

An intravenous formulation may be prepared as follows:

    ______________________________________                                        Active ingredient     100    mg                                               Isotonic saline       1,000  ml                                               ______________________________________                                    

The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 ml per minute.

Assay Experiments Assay Example 1

The following chromogenic assay procedure was used to identify andevaluate inhibitors of recombinant human secreted phospholipase A₂. Theassay described herein has been adapted for high volume screening using96 well microtiter plates. A general description of this assay method isfound in the article, "Analysis of Human Synovial Fluid Phospholipase A₂on Short Chain Phosphatidylcholine-Mixed Micelles: Development of aSpectrophotometric Assay Suitable for a Microtiterplate Reader", byLaure J. Reynolds, Lori L. Hughes, and Edward A Dennis, AnalyticalBiochemistry, 204, pp. 190-197, 1992 (the disclosure of which isincorporated herein by reference):

Reagents:

REACTION BUFFER

CaCl₂.2H₂ O (1.47 g/L)

KCl (7.455 g/L)

Bovine Serum Albumin (fatty acid free) (1 g/L) (Sigma A-7030, product ofSigma Chemical Co. St. Louis Mo., USA)

TRIS HCl (3.94 g/L)

pH 7.5 (adjust with NaOH)

ENZYME BUFFER

0.05 NaOAc.3H₂ O, pH 4.5

0.2 NaCl

Adjust pH to 4.5 with acetic acid

DTNB--5,5'-dithiobis-2-nitrobenzoic acid

RACEMIC DIHEPTANOYL THIO--PC

racemic1,2-bis(heptanoylthio)-1,2-dideoxy-sn-glycero-3-phosphorylcholine

TRITON X-100™ prepare at 6.249 mg/ml in reaction buffer to equal 10 uM.

REACTION MIXTURE

A measured volume of racemic dipheptanoyl thio PC supplied in chloroformat a concentration of 100 mg/ml is taken to dryness and redissolved in10 millimolar TRITON X 100™ nonionic detergent aqueous solution.Reaction Buff added to the solution, then DTNB to give the ReactionMixture.

The reaction mixture thus obtained contains 1 m diheptanoly thio-PCsubstrate, 0.29 mm Triton X-100™ detergent, and 0.12 mm DTMB in abuffered aqueous solution at pH 7.5.

Assay Procedure:

1. Add 0.2 ml reaction mixture to all wells;

2. Add 10 ul test compound (or solvent blank) to appropriate wells, mix20 seconds;

3. Add 50 nanograms of sPLA₂ (10 microliters) to appropriate wells;

4. Incubate plate at 40° C. for 30 minutes;

5. Read absorbance of wells at 405 nanometers with an automatic platereader.

All compounds were tested in triplicate. Typically, compounds weretested am a final concentration of 5 ug/ml. Compounds were consideredactive when they exhibited 40% inhibition or greater compared touninhibited control reactions when measured at 405 nanometers. Lack ofcolor development at 405 nanometers evidenced inhibition. Compoundsinitially found to be active were reassayed to confirm their activityand, if sufficiently active, IC₅₀ values were determined. Typically, theIC₅₀ values (see, Table I, below) were determined by diluting testcompound serially two-fold such that the final concentration in thereaction ranged from 45 ug/mL to 0.35 ug/ml. More potent inhibitorsrequired significantly greater dilution. In all cases, % inhibitionmeasured at 405 nanometers generated by enzyme reactions containinginhibitors relative to the uninhibited control reactions was determined.Each sample was titrated in triplicate and result values were averagedfor plotting and calculation of IC₅₀ values. IC₅₀ were determined byplotting log concentration versus inhibition values in the range from10-90% inhibition.

    ______________________________________                                        Results of Human Secreted Phospholipase A.sub.2 Inhibition Tests                                Inhibition of human                                                           secreted PLA.sub.2                                          Compound of       μM IC.sub.50 ± mean                                   Example number    deviation (3-4 tests)                                       ______________________________________                                        1 (acid form of acetamide)                                                                      0.013 ± 0.002                                            2 (acid form of acetamide)                                                                      0.033 ± 0.003                                            3 (acid form of acetamide)                                                                      0.035 ± 0.008                                            4 (acid form of hydrazide)                                                                      0.20 ± 0.09                                              ______________________________________                                    

Assay Example 2

Method:

Male Hartley strain guinea pigs (500-700 g) were killed by cervicaldislocation and their heart and lungs removed intact and placed inaerated (95% 0₂ :5% CO₂) Krebs buffer. Dorsal pleural strips (4×1×25 mm)were dissected from intact parenchymal segments (8×4×25 mm) cut parallelto the outer edge of the lower lung lobes. Two adjacent pleural strips,obtained from a single lobe and representing a single tissue sample,were tied at either end and independently attached to a metal supportrod. One rod was attached to a Grass force-displacement transducer(Model FTO3C, product of Grass Medical Instruments Co., Quincy, Mass.,USA). Changes in isometric tension were displayed on a monitor andthermal recorder (product of Modular Instruments, Malvern, Pa.). Alltissues were placed in 10 ml jacketed tissue baths maintained at 37° C.The tissue baths were continuously aerated and contained a modifiedKrebs solution of the following composition (millimolar) NaCl, 118.2;KCl, 4.6; CaCl₂.2H₂ O, 2.5; MgSO₄.7H₂ O, 1.2; NaHCO₃, 24.8; KH₂ PO₄,1.0; and dextrose, 10.0. Pleural strips from the opposite lobes of thelung were used for paired experiments. Preliminary data generated fromtension/response curves demonstrated that resting tension of 800 mg wasoptimal The tissues were allowed to equilibrate for 45 min. as the bathfluid was changed periodically.

Cumulative concentration-response curves:

Initially tissues were challenged 3 times with KCl (40 mM) to testtissue viability and to obtain a consistent response. After recordingthe maximal response to KCl, the Elssues were washed and allowed toreturn to baseline before the next challenge. Cumulativeconcentration-response curves were obtained from pleural strips byincreasing the agonist concentration (sPLA₂) in the tissue bath byhalf-log₁₀ increments while the previous concentration remained incontact with the tissues (Ref.1, supra.) Agonist concentration wasincreased after reaching the plateau of the contraction elicited by thepreceding concentration. One concentration-response curve was obtainedfrom each tissue. To minimize variability between tissues obtained fromdifferent animals, contractile responses were expressed as a percentageof the maximal response obtained with the final KCl challenge. Whenstudying the effects of various drugs on the contractile effects ofsPLA₂, the compounds and their respective vehicles were added to thetissues 30 min. prior to starting the sPLA₂ concentration-responsecurves.

Statistical analysis;

Data from different experiments were pooled and presented as apercentage of the maximal KCl responses (mean±S.E.). To estimate thedrug induced rightward shifts in the concentration response curves, thecurves were analyzed simultaneously using statistical nonlinear modelingmethods similar to those described by Waud (1976), Equation 26, p. 163,(Ref.2). The model includes four parameters: the maximum tissue responsewhich was assumed the same for each curve, the ED₅₀ for the controlcurve, the steepness of the curves, and the PA₂, the concentration ofantagonist that requires a two-fold increase in agonist to achieve anequivalent response. The Schild slope was determined to be 1, usingstatistical nonlinear modeling methods similar to those described byWaud 1976), Equation 27, p. 164 (Ref. 2). The Schild slope equal to 1indicates the model is consistent with the assumptions of a competitiveantagonist; therefore, the pA2 may be interpreted as the apparent K_(B),the dissociation constant of the inhibitor.

To estimate the drug-induced suppression of the maximal responses, sPLA₂responses (10 ug/ml) were determined in the absence and presence ofdrug, and percent suppression was calculated for each pair of tissues.Representative examples of inhibitory activities are presented in Table2, below.

Ref. 1--van, J. M.: Cumulative dose-response curves. II. Technique forthe making of dose-response curves in isolated organs and the evaluationof drug parameters. Arch. Int. Pharmacodyn. Ther., 143: 299-330, 1963.

Ref. 2--Waud, D.: Analysis of dose-response relationships. in Advancesin General and Cellular Pharmacology eds Narahashi, Bianchi 1:145-178,1976.

Results of Human Secreted Phospholipase A₂ Inhibition Tests on guineapig lung tissue

                  TABLE II                                                        ______________________________________                                                      Tissue test                                                     Compound of   secreted PLA.sub.2                                              Example No.   Apparent K.sub.B μM                                          ______________________________________                                        1             0.39 ± 0.12                                                  2             1.47 ± 0.34                                                  3             0.415 ± 0.051                                                4             1.67 ± 0.28                                                  ______________________________________                                    

While the present invention has been illustrated above by certainspecific embodiments, in is not intended that these specific examplesshould limit the scope of the invention as described in the appendedclaims.

We claim:
 1. A 1H-indole-1-acetamide compound or a pharmaceuticallyacceptable salt or solvate derivative thereof; wherein said compound isrepresented by the formula; ##STR33## wherein; R₂ is cyclopropyl,methyl, or ethyl;R₆ and R₇ are independently selected from hydrogen or anon-interfering substituent selected from the group consisting of C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl,C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl, phenyl, toluyl, xylenyl,biphenyl, C₁ -C₆ alkoxy, C₂ -C₆ alkenyloxy, C₂ -C₆ alkynyloxy, C₂ -C₁₂alkoxyalkyl, C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₁ -C₆ haloalkoxy, C₁ -C₆haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆alkyl), --(C(CH₂)_(n) --O--(C₁ -C₆ alkyl), benzyloxy, phenoxy,phenylthio, --(CONHSO₂ R), --CHO, amino, amidino, bromo, carbamyl,carboxyl, ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro, cyano,cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido,hydroxy, hydroxyamino, iodo, nitro, phosphono, --SO₃ H, thioacetal,thiocarbonyl, and C₁ -C₆ carbonyl where n is from 1 to 8; or the group--(L_(a))-(acidic group); where --(L_(a))--, is an acid linker having anacid linker length of 1 to 10; provided, that at least one of R₆ and R₇must be the group, --(L_(a))-(acidic group); R₄ and R₅ are eachindependently selected from hydrogen or a non-interfering substituentselected from the group consisting of C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₂ -C₆alkenyloxy, C₂ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂-C₁₂ alkylamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁ -C₆alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, C₁ -C₆ haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n)--O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R),--CHO, amino, amidino, bromo, carbamyl, carboxyl, ethoxycarbonyl,--(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino,hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro,phosphono, --SO₃ H, thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl wheren is from 1 to 8; or a carbocyclic radical or carbocyclic radicalsubstituted with said non-interfering substituents, said carbocyclicradical selected from the group consisting of cycloalkyl, cycloalkenyl,phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl,indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl,acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and relatedbibenzylyl homologues represented by the formula (bb), ##STR34## where nis a number from 1 to 8; or a heterocyclic radical or a heterocyclicradical substituted with said non-interfering substituents, saidheterocyclic radical selected from the group consisting of pyrrolyl,furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl,isoxaxolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl,norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl,dibenzothiophenyl, indazolyl, imidazo(1,2-A)pyridinyl, benzotriazolyl,anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl,pyridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl,phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl,quinazolinyl, and quinoxalinyl; and R₁₀ is a radical independentlyselected from halo, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, --S--(C₁ -C₁₀ alkyl),and C₁ -C₁₀ haloalkyl, and t is a number from 0 to
 5. 2. The compound ofclaim 1 wherein;(i) X is oxygen; (ii) R₂ is selected from the group;halo, cyclopropyl, methyl, and ethyl; (iii) R₃ has as a linking group--(L)-- an alkylene chain of 1 or 2 carbon atoms and R₈₀ is selectedfrom the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl,norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl,terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl,and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologuesrepresented by the formula (bb), ##STR35## where n is a number from 1 to8; (iv) R₆ or R₇ have an (acidic group) on the group --(L_(a))-(acidicgroup) selected from: ##STR36## where n is 1 to 8, R₈₉ is a metal or C₁-C₁₀ alkyl, and R₉₉ is hydrogen or C₁ -C₁₀ alkyl; and (v) R₄ and R₅ areeach independently selected from hydrogen and non-interferingsubstituents, with the non-interfering substituents being selected fromthe group consisting of the following: C₁ -C₆ alkyl, C₁ -C₆ alkenyl, C₁-C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₁ -C₆alkenyloxy, C₁ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁-C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, C₂ -C₆ haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n)--O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R),--CHO, amino, amidino, bromo, carbamyl, carboxyl, ethoxycarbonyl,--(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino,hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro,phosphono, --SO₃, thioacetal thiocarbonyl, and C₁ -C₆ carbonyl; where nis from 1 to
 8. 3. The compound of claim 2, wherein,(A) for (iii), thegroup R₃ is selected from the group consisting of ##STR37## where R₁₀ isa radical independently selected from halo, C₁ -C₁₀ alkyl, C₁ -C₁₀alkoxy, --S--(C₁ -C₁₀ alkyl), and C₁ -C₁₀ haloalkyl, q is a number from0 to 4, and t is a number from 0 to 5; and (B) for (iii) the linkinggroup --(L)-- of R₃ is selected from the group consisting of:

    --C.tbd.C--,

    --CH═CH--,

    --CH.sub.2 --,

    --(CH.sub.2).sub.2 --, ##STR38##

    --(CH.sub.2).sub.S --S--,

    --(CH.sub.2).sub.S --O--,

and ##STR39## where s=0 or 1; (C) for (iv) the (acidic group) of R₆ orR₇ is selected from:

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O) (OH).sub.2.


4. The compound of claim 1 wherein R₇ comprises an acidic group and hasan acid linker with an acid linker length of 2 or 3 and the acid linkergroup, --(L_(a))--, for R₇ is represented by the formula; ##STR40##where Q is selected from the group --(CH₂)--, --O--, --NH--, and --S--,and R₈₄ and R₈₅ are each independently selected from hydrogen, C₁ -C₁₀alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl,and halo.
 5. The compound of claim 4 wherein R₇ comprises an acidicgroup and the acid linker group, --(L_(a))--, for R₇ is selected fromthe group consisting of; ##STR41## where R is H or C₁ -C₄ alkyl.
 6. Thecompound of claim 1 wherein R₆ comprises an acidic group and has an acidlinker with an acid linker length of 3 to 10 atoms and the acid linkergroup, --(L_(a))--, for R₆ is selected from; ##STR42## where r is anumber from 1 to 7, s is 0 or 1, and Q is selected from the group--(CH₂)--, --O--, --NH--, and --S--, and R₈₄ and R₈₅ are eachindependently selected from hydrogen, C₁ -C₁₀ alkyl, aryl, C₁ -C₁₀alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl, and halo.
 7. Thecompound of claim 6 wherein the acid linker, --(L_(a))--, for R₆ isselected from group consisting of; ##STR43## wherein; R is hydrogen orC₁ -C₄ alkyl, R₈₄ and R₈₅ are each independently selected from hydrogen,C₁ -C₁₀ alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy,ethoxycarbonyl, and halo.
 8. A 1H-indole-1-hydrazide compound or apharmaceutically acceptable salt or solvate derivative thereof; whereinsaid compound is represented by the formula; ##STR44## wherein: R₂ iscyclopropyl, methyl, or ethyl;R₆ and R₇ are independently selected fromhydrogen or a non-interfering substituent selected from the groupconsisting of C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkenyl, C₇ -C₁₂aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl,phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₂ -C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₁ -C₆haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n) --O--(C₁ -C₆ alkyl),benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R), --CHO, amino, amidino,bromo, carbamyl, carboxyl, ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro,cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino,hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, --SO₃ H,thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl where n is from 1 to 8; orthe group --(L_(a))-(acidic group); where --(L_(a))--, is an acid linkerhaving an acid linker length of 1 to 10; provided, that at least one ofR₆ and R₇ must be the group, --(L_(a))-(acidic group); R₄ and R₅ areeach independently selected from hydrogen or a non-interferingsubstituent selected from the group consisting of C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁-C₆ alkoxy, C₂ -C₆ alkenyloxy, C₂ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl,C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₁ -C₆ haloalkoxy, C₁ -C₆haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆alkyl), --(CH₂)_(n) --O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio,--(CONHSO₂ R), --CHO, amino, amidino, bromo, carbamyl, carboxyl,ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, --SO₃ H, thioacetal, thiocarbonyl,and C₁ -C₆ carbonyl where n is from 1 to 8; or a carbocyclic radical orcarbocyclic radical substituted with said non-interfering substituents,said carbocyclic radical selected from the group consisting ofcycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl,bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl,diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, andanthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologuesrepresented by the formula (bb), ##STR45## where n is a number from 1 to8; or a heterocyclic radical or a heterocyclic radical substituted withsaid non-interfering substituents said heterocyclic radical selectedfrom the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl,imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl,benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl,indazolyl, imidazo(1,2-A)pyridinyl, benzotriazolyl, anthranilyl,1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl,dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl,phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl,quinazolinyl, and quinoxalinyl; and R₁₀ is a radical independentlyselected from halo, C₁ -C₁₀ alkyl, C₁ -C₁₀ alkoxy, --S--(C₁ -C₁₀ alkyl),and C₁ -C₁₀ haloalkyl, and t is a number from 0 to
 5. 9. The compound ofclaim 8 wherein;(i) X is oxygen; (ii) R₂ is selected from the group;halo, cyclopropyl, methyl, and ethyl; (iii) R₃ has as a linking group--(L)-- an alkylene chain of 1 or 2 carbon atoms and R₈₀ is selectedfrom the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl,norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl,terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl,and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologuesrepresented by the formula (bb), ##STR46## where n is a number from 1 to8; (iv) R₆ or R₇ have an (acidic group) on the group --(L_(a))-(acidicgroup) selected from: ##STR47## where n is 1 to 8, R₈₉ is a metal or C₁-C₁₀ alkyl, and R₉₉ is hydrogen or C₁ -C₁₀ alkyl; and (v) R₄ and R₅ areeach independently selected from hydrogen and non-interferingsubstituents, with the non-interfering substituents being selected fromthe group consisting of the following: C₁ -C₆ alkyl, C₁ -C₆ alkenyl, C₁-C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₁ -C₆alkenyloxy, C₁ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁-C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, C₂ -C₆ haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n)--O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R),--CHO, amino, amidino, bromo, carbamyl, carboxyl, ethoxycarbonyl,--(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino,hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro,phosphono, --SO₃ H, thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl; wheren is from 1 to
 8. 10. The compound of claim 9, wherein,(A) for (iii),the group R₃ is selected from the group consisting of ##STR48## whereR₁₀ is a radical independently selected from halo, C₁ -C₁₀ alkyl, C₁-C₁₀ alkoxy, --S--(C₁ -C₁₀ alkyl), and C₁ -C₁₀ haloalkyl, q is a numberfrom 0 to 4, and t is a number from 0 to 5; and (B) for (iii) thelinking group --(L)-- of R₃ is selected from the group consisting of:

    --C.tbd.C--,

    --CH═CH--,

    --CH.sub.2 --,

    --(CH.sub.2).sub.2 --, ##STR49##

    --(CH.sub.2).sub.S --S--,

    --(CH.sub.2).sub.S --O--,

and ##STR50## (C) for (iv) the (acidic group) of R₆ or R₇ is selectedfrom:

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O)(OH).sub.2.


11. The compound of claim 8 wherein R₇ comprises an acidic group and hasan acid linker with an acid linker length of 2 or 3 and the acid linkergroup, --(L_(a))--, for R₇ is represented by the formula; ##STR51##where Q is selected from the group --(CH₂)--, --O--, --NH--, and --S--,and R₈₄ and R₈₅ are each independently selected from hydrogen, C₁ -C₁₀alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl,and halo.
 12. The ccmpound of claim 11 wherein the acid linker group,--(L_(a))--, for R₇ is selected from the group consisting of; ##STR52##where R is H or C₁ -C₄ alkyl.
 13. The compound of claim 8 wherein R₆comprises an acidic group and has an acid linker with an acid linkerlength of 3 to 10 atoms and the acid linker group, --(L_(a))--, for R₆is selected from; ##STR53## where r is a number from 1 to 7, s is 0 or1, and Q is selected from the group --(CH₂)--, --O--, --NH--, and --S--,and R₈₄ and R₈₅ are each independently selected from hydrogen, C₁ -C₁₀alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl,and halo.
 14. The compound cf claim 13 wherein the acid linker,--(L_(a))--, for R₆ is selected from group consisting of; ##STR54##wherein; R is hydrogen or C₁ -C₄ alkyl, R₈₄ and R₈₅ are eachindependently selected from hydrogen, C₁ -C₁₀ alkyl, aryl, C₁ -C₁₀alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl, and halo.
 15. A1H-indole-1-acetamide compound or a pharmaceutically acceptable salt orsolvate thereof; wherein said compound is represented by the formula(IV); ##STR55## wherein; R₁₃ is selected from groups (a), (b) and (c)where;(a) is C₇ -C₂₀ alkyl, C₇ -C₂₀ alkenyl, C₇ -C₂₀ alkynyl; or acarbocyclic radical selected from the group cycloalkyl, cycloalkenyl,phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl,indenyl, stilbenyl, terephenylyl, diphenylethylenyl,phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl,bibenzylyl and related bibenzylyl homologues represented by the formula(bb), ##STR56## where n is a number from 1 to 8; or (b) is a member of(a) substituted with one or more independently selected non-interferingsubstituents selected from the group consisting of C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁-C₆ alkoxy, C₂ -C₆ alkenyloxy, C₂ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl,C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₂ -C₆ haloalkoxy, C₁ -C₆haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆alkyl), --(CH₂)_(n) --O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio,--(CONHSO₂ R), --CHO, amino, amidino, bromo, carbamyl, carboxyl,ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, --SO₃ H, thioacetal, thiocarbonyl,and C₁ -C₆ carbonyl; where R is H or C₁ -C₄ alkyl and n is from 1 to 8;(c) is the group --(L₁)--R₈₁ ; where, --(L₁)-- is a divalent linkinggroup having the formula; ##STR57## where, R₈₄ and R₈₅ are eachindependently selected from hydrogen, C₁ -C₁₀ alkyl, carboxyl,ethoxycarbonyl, or halo;p is 1 to 5, Z is a bond, --(CH₂)--, --O--,--N(C₁ -C_(1O) alkyl)--, --NH--, or --S--; andwhere R₈₁ is a groupselected from (a) or (b); R₁₂ is hydrogen, halo, C₁ -C₃ alkyl, C₃ -C₄cycloalkyl, C₃ -C₄ cycloalkenyl, --O--(C₁ -C₂ alkyl), or --S--(C₁ -C₂alkyl); R₁₇ is selected from hydrogen, a non-interfering substituent, orthe group, --(L_(a))-(acidic group), wherein the acid linker --(L_(a))--has an acid linker length of 2 or 3 atoms and is represented by theformula; ##STR58## where Q is selected from the group --(CH₂)--, --O--,--NH--, and --S--; R₈₄ and R₈₅ are each independently selected fromhydrogen, C₁ -C₁₀ alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl,hydroxy, and halo; and the acidic group is selected from

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O)(OH).sub.2,

R₁₆ is selected from hydrogen or a non-interfering substituent selectedfrom the group consisting of C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₂ -C₆alkenyloxy, C₂ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁-C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, C₂ -C₆ haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n)--O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R),--CHO, amino, amidino, bromo, carbamyl, carboxyl, ethoxycarbonyl,--(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino,hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro,phosphono, --SO₃ H, thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl, whereR is H or C₁ -C₄ alkyl and n is from 1 to 8; or the group,--(L_(a))-(acidic group), wherein the acid linker --(L_(a))-- has anacid linker length of 3 to 10 atoms and the acid linker group,--(L_(a))-- is; ##STR59## where r is a number from 1 to 7, s is 0 or 1,and Q is selected from the group --(CH₂)--, --O--, --NH--, and --S--;and R₈₄ and R₈₅ are each independently selected from hydrogen, C₁ -C₁₀alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl,and halo; and the acidic group is selected from

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O)(OH).sub.2,

provided that at least one of R₁₆ or R₁₇ must be the group,--(L_(a))-(acidic group); R₁₄ and R₁₅ are each independently selectedfrom hydrogen or a non-interfering substituent selected from the groupconsisting of C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₇ -C₁₂aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl,phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₂ -C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₂ -C₆haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl ), --(CH₂)_(n) --O--(C₁ -C₆ alkyl),benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R), --CHO, amino, amidino,bromo, carbamyl, carboxyl, ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro,cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino,hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, --SO₃ H,thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl; where R is H or C₁ -C₄alkyl and n is from 1 to
 8. 16. A 1H-indole-1-acetic acid hydrazidecompound or a pharmaceutically acceptable salt or solvate thereof;wherein said compound is represented by the formula (V): ##STR60##wherein; R₁₃ is selected from groups (a), (b) and (c) where;(a) is C₇-C₂₀ alkyl, C₇ -C₂₀ alkenyl, C₇ -C₂₀ alkynyl; or a carbocyclic radicalselected from the group cycloalkyl, cycloalkenyl, phenyl, naphthyl,norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl,terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl,and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologuesrepresented by the formula (bb), ##STR61## where n is a number from 1 to8; or (b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents selected from the group consistingof C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₇ -C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl, phenyl, toluyl,xylenyl, biphenyl, C₁ -C₆ alkoxy, C₂ -C₆ alkenyloxy, C₂ -C₆ alkynyloxy,C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₂ -C₆haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n) --O--(C₁ -C₆ alkyl),benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R), --CHO, amino, amidino,bromo, carbamyl, carboxyl, ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro,cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino,hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, --SO₃ H,thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl; where R is H or C₁ -C₄alkyl and n is from 1 to 8; (c) is the group --(L₁)--R₈₁ ; where,--(L₁)-- is a divalent linking group having the formula; ##STR62##where, R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy,ethoxycarbonyl, and halo;p is 1 to 5, Z is a bond, --(CH₂)--, --O--,--N(C₁ -C₁₀ alkyl)--, --NH--, or --S--; andwhere R₈₁ is a group selectedfrom (a) or (b); R₁₂ is hydrogen, halo, C₁ -C₃ alkyl, C₃ -C₄ cycloalkyl,C₃ -C₄ cycloalkenyl, --O--(C₁ -C₂ alkyl), or --S--(C₁ -C₂ alkyl); R₁₇ isselected from hydrogen, a non-interfering substituent, or the group,--(L_(a))-(acidic group), wherein the acid linker --(L_(a))-- has anacid linker length of 2 or 3 atoms and is represented by the formula;##STR63## where Q is selected from the group --(CH₂)--, --O--, --NH--,and --S--; R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, hydroxy, and halo;and the acidic group is selected from

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O)(OH).sub.2,

R₁₆ is selected from hydrogen or a non-interfering substituent selectedfrom the group consisting of C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₇ -C₁₂ aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₂ -C₆alkenyloxy, C₂ -C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂alkoxyalkyloxy, C₂ -C₁₂ alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂ -C₁₂ alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁-C₆ alkylthio, C₂ -C₁₂ alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, C₂ -C₆ haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆haloalkyl, C₁ -C₆ hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n)--O--(C₁ -C₆ alkyl), benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R),--CHO, amino, amidino, bromo, carbamyl, carboxyl, ethoxycarbonyl,--(CH₂)_(n) --CO₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino,hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro,phosphono, --SO₃ H, thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl, whereR is H or C₁ -C₄ alkyl and n is from 1 to 8; or the group,--(L_(a))-(acidic group), wherein the acid linker --(L_(a))-- has anacid linker length of 3 to 10 atoms and the acid linker group,--(L_(a))-- is; ##STR64## where r is a number from 1 to 7, s is 0 or 1,and Q is selected from the group --(CH₂)--, --O--, --NH--, and --S--;and R₈₄ and R₈₅ are each independently selected from hydrogen, C₁ -C₁₀alkyl, aryl, C₁ -C₁₀ alkaryl, C₁ -C₁₀ aralkyl, carboxy, ethoxycarbonyl,and halo; and the acidic group is selected from

    --CO.sub.2 H,

    --SO.sub.3 H,

    --P(O)(OH).sub.2,

provided that at least one of R₁₆ or R₁₇ must be the group,--(L_(a))-(acidic group); R₁₄ and R₁₅ are each independently selectedfrom hydrogen or a non-interfering substituent selected from the groupconsisting of C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₇ -C₁₂aralkyl, C₇ -C₁₂ alkaryl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl,phenyl, toluyl, xylenyl, biphenyl, C₁ -C₆ alkoxy, C₂ -C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂ -C₁₂ alkoxyalkyl, C₂ -C₁₂ alkoxyalkyloxy, C₂ -C₁₂alkylcarbonyl, C₂ -C₁₂ alkylcarbonylamino, C₂ -C₁₂ alkoxyamino, C₂ -C₁₂alkoxyaminocarbonyl, C₁ -C₁₂ alkylamino, C₁ -C₆ alkylthio, C₂ -C₁₂alkylthiocarbonyl, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, C₂ -C₆haloalkoxy, C₁ -C₆ haloalkylsulfonyl, C₁ -C₆ haloalkyl, C₁ -C₆hydroxyalkyl, --C(O)O(C₁ -C₆ alkyl), --(CH₂)_(n) --O--(C₁ -C₆ alkyl),benzyloxy, phenoxy, phenylthio, --(CONHSO₂ R), --CHO, amino, amidino,bromo, carbamyl, carboxyl, ethoxycarbonyl, --(CH₂)_(n) --CO₂ H, chloro,cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino,hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, --SO₃ H,thioacetal, thiocarbonyl, and C₁ -C₆ carbonyl; where R is H or C₁ -C₄alkyl and n is from 1 to
 8. 17. A pharmaceutical formulation comprisinga 1H-indole-1-acetamide as claimed in claim 1 together with apharmaceutically acceptable carrier or diluent therefor.
 18. Apharmaceutical formulation comprising a 1H-indole-1-hydrazide as claimedin claim 8 together with a pharmaceutically acceptable carrier ordiluent therefor.
 19. A method of treating a mammal to alleviate thepathological effects of septic shock, adult respiratory distresssyndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, andrheumatoid arthritis; wherein the method comprises administration tosaid mammal of at least one 1H-indole-1-acetamide as claimed in claim 1in an amount sufficient to inhibit sPLA₂ mediated release of fatty acidand to thereby inhibit or prevent the arachidonic acid cascade and itsdeleterious products.
 20. A method of treating a mammal to alleviate thepathological effects of septic shock, adult respiratory distresssyndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, andrheumatoid arthritis; wherein the menhod comprises administration tosaid mammal of at least one 1H-indole-1-acetic acid hydrazide as claimedin claim 8 in an amount sufficient to inhibit sPLA₂ mediated release offatty acid and to thereby inhibit or prevent the arachidonic acidcascade and its deleterious products.
 21. A 1H-indole-1-functionalcompound or a pharmaceutically acceptable salt thereof; wherein saidcompound is selected from the group represented by the formulae:##STR65##